tbuckley/cabot-search huggingface dataset:
Burden of Rare Genetic Variants in Spontaneous Coronary Artery Dissection With High-risk Features
Authors: Yu Wang, Andrew Starovoytov, Andrea M. Murad, Kristina L. Hunker, Liam R. Brunham, Jun Z. Li, Jacqueline Saw, Santhi K. Ganesh
Journal: JAMA Cardiology (2022)

Importance The emerging genetic basis of spontaneous coronary artery dissection (SCAD) has been defined as both partially complex and monogenic in some patients, involving variants predominantly in genes known to underlie vascular connective tissue diseases (CTDs). The effect of these genetic influences has not been defined in high-risk SCAD phenotypes, and the identification of a high-risk subgroup of individuals may help to guide clinical genetic evaluations of SCAD. Objective To identify and quantify the burden of rare genetic variation in individuals with SCAD with high-risk clinical features. Design, Setting, and Participants Whole-exome sequencing (WES) was performed for subsequent case-control association analyses and individual variant annotation among individuals with high-risk SCAD. Genetic variants were annotated for pathogenicity by in-silico analysis of genes previously defined by sequencing for vascular CTDs and/or SCAD, as well as genes prioritized by genome-wide association study (GWAS) and colocalization of arterial expression quantitative trait loci. Unbiased genome-wide association analysis of the WES data was performed by comparing aggregated variants in individuals with SCAD to healthy matched controls or the Genome Aggregation Database (gnomAD). This study was conducted at a tertiary care center. Individuals in the Canadian SCAD Registry genetics study with a high-risk SCAD phenotype were selected and defined as peripartum SCAD, recurrent SCAD, or SCAD in an individual with family history of arteriopathy. Main Outcomes and Measures Burden of genetic variants defined by DNA sequencing in individuals with high-risk SCAD. Results This study included a total of 336 participants (mean [SD] age, 53.0 [9.5] years; 301 female participants [90%]). Variants in vascular CTD genes were identified in 17.0% of individuals (16 of 94) with high-risk SCAD and were enriched (OR, 2.6; 95% CI, 1.6-4.2; P = 7.8 × 10 −4 ) as compared with gnomAD, with leading significant signals in COL3A1 (OR, 13.4; 95% CI, 4.9-36.2; P = 2.8 × 10 −4 ) and Loeys-Dietz syndrome genes (OR, 7.9; 95% CI, 2.9-21.2; P = 2.0 × 10 −3 ). Variants in GWAS-prioritized genes, observed in 6.4% of individuals (6 of 94) with high-risk SCAD, were also enriched (OR, 3.6; 95% CI, 1.6-8.2; P = 7.4 × 10 −3 ). Variants annotated as likely pathogenic or pathogenic occurred in 4 individuals, in the COL3A1 , TGFBR2 , and ADAMTSL4 genes. Genome-wide aggregated variant testing identified novel associations with peripartum SCAD. Conclusions and Relevance In this genetic study, approximately 1 in 5 individuals with a high-risk SCAD phenotype harbored a rare genetic variant in genes currently implicated for SCAD. Genetic screening in this subgroup of individuals presenting with SCAD may be considered.
Treatment for Appendicitis—Reply
Authors: David R. Flum, Sarah E. Monsell
Journal: JAMA Surgery (2022)

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Errors in Terminology, Data Query, and Prevalence Rates
Authors: Peter Barr, Tim Bigdeli, Jacquelyn Meyers
Journal: JAMA Psychiatry (2022)

differences between our corrected and original estimates and between those by Kuplicki and Thompson to our use of the PheWAS statistical package (as detailed in the article Supplement), which may need maps expanded to additional source vocabularies, similar to other programs. 5 We included more details of our analytic choices and their limitations in the corrected Supplement.We believe this can serve as a useful guide for readers who want to use this relatively new data resource.Importantly, while we were able to identify more participants with a diagnosis, we observed similar patterns of comorbidity and relationships with sociodemographic correlates.We are grateful for the authors' comments on our article.All of Us provides a rich source of data with various nuances to be considered.We hope this lesson is taken to heart by all those interested in working with this new and complex resource.We have requested that our original article be corrected to include the term diagnoses vs disorders, our revised methods of analysis, and corrected estimates of prevalence of diagnoses in the title, text, Tables, Figure , and Supplement.
Long-term Outcomes Among Men Undergoing Active Surveillance for Prostate Cancer in Sweden
Authors: Eugenio Ventimiglia, Anna Bill-Axelson, Ola Bratt, Francesco Montorsi, Pär Stattin, Hans Garmo
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The long-term outcomes among men with prostate cancer (PC) whose disease is managed with active surveillance (AS) remains unknown. <h3>Objective</h3> To develop a simulation model with a 30-year follow-up for men with PC managed with AS. <h3>Design, Setting, and Participants</h3> In this cohort study, a state transition model was created using data from Prostate Cancer data Base Sweden (PCBaSe) on 23 655 men diagnosed with PC and managed with deferred treatment to estimate treatment trajectories. A simulation was performed with 100 000 men in each combination of age at diagnosis, Charlson Comorbidity Index, and PC risk with a follow-up of 30 years. <h3>Main Outcomes and Measures</h3> Death from PC and death from other causes were estimated, and the proportion of time without active PC treatment was assessed until date of death or age 85 years. <h3>Results</h3> This study included 23 655 men from PCBaSe with a median age at diagnosis of 69 years (IQR, 64-74 years). Of these, 16 177 men underwent active surveillance for PC and 7478 underwent watchful waiting. The proportion of men who were diagnosed at age 55 years and died of PC before age 85 years was 9% for very low-risk PC, 13% for low-risk PC, and 15% for intermediate-risk PC. Among men with a Charlson Comorbidity Index of 0 who were diagnosed at age 70 years, the corresponding percentages were 3%, 6%, and 7%, respectively. The mean proportion of remaining life-years without active PC treatment for men diagnosed at age 55 years was 12 of 25 years (48%) for very low-risk PC, 9 of 25 years (36%) for low-risk PC, and 7 of 25 (29%) for intermediate-risk PC. For men aged 70 years, the corresponding numbers were 10 of 13 years (77%), 9 of 13 years (66%), and 8 of 13 years (60%), respectively. Men with intermediate-risk PC who were younger than 60 years at diagnosis had a high risk of PC death (12%-15%) and fewer remaining life-years without active PC treatment (29%-33%). In contrast, men with low-risk PC who were older than 65 years at diagnosis had a lower risk of PC death (3%-5%) and more remaining life-years without active PC treatment (62%-77%). <h3>Conclusions and Relevance</h3> The findings of this Swedish cohort study suggest that active surveillance may be a safe strategy for disease management among men with PC who were older than 65 years at diagnosis.
Computer Surveillance of Hospital-Acquired Infections and Antibiotic Use
Authors: R. Scott Evans
Journal: JAMA (1986)

Surveillance of hospital-acquired infections and antibiotic use is required of US hospitals. The time and cost needed to actively perform this surveillance can be extensive. We developed a computerized infectious disease monitor that automatically generates four types of surveillance "alerts" for patients (1) with hospital-acquired infections, (2) not receiving antibiotics to which their pathogens are susceptible, (3) who could be receiving less expensive antibiotics, or (4) who are receiving prophylactic antibiotics too long. Surveillance personnel using computer screening for two months found more hospital-acquired infections when compared with our traditional surveillance methods, while requiring only 35% of the time. In addition, alerts from the computer identified 37 patients not receiving appropriate antibiotics, 31 patients who could have been receiving less expensive antibiotics, and 142 patients, during one month, receiving prolonged cephalosporin prophylaxis. Computer screening can help focus the activities and improve the efficiency of hospital surveillance personnel. (<i>JAMA</i>1986;256:1007-1011)
Growth Hormone Neurosecretory Dysfunction
Authors: Bessie E. Spiliotis
Journal: JAMA (1984)

Pulsatile growth hormone (GH) secretion was assessed in a subgroup of short children to determine whether they had GH secretory abnormalities, and these results were compared with those of normal and GH-deficient children. This subgroup of children was defined as having GH neurosecretory dysfunction and met the following criteria: height, less than first percentile; growth velocity, 4 cm/yr or less; bone age, two or more years behind chronological age, normal findings from provocative GH tests (peak, ≥10 ng/mL), low somatomedin-C level, and abnormal 24-hour GH secretory patterns. When compared with controls, both children with GH neurosecretory dysfunction and GH-deficient patients had a significant decrease in parameters relating to the total GH secretion during the 24-hour period. As with GH-deficient children, the group with GH neurosecretory dysfunction more than doubled their growth velocity after replacement therapy with exogenous human GH during the first year of treatment. As a result of these detailed studies on pulsatile GH secretion, we suggest that there is a spectrum of GH secretory abnormalities from absolute deficiency to an intermittent irregularity in GH secretion. (<i>JAMA</i>1984;251:2223-2230)
HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium.
Authors: H S Taylor, A Arici, D Olive, P Igarashi
Journal: Journal of Clinical Investigation (1998)

Previous studies have shown that triggering multiple myeloma (MM) cells via CD40 induces IL-6-mediated autocrine growth as well as increased expression of cell surface adhesion molecules including CD11a, CD11b, CD11c, and CD18. In this study, we generated the 5E2 mAb which targets an antigen that is induced upon CD40 ligand (CD40L) activation of MM cells. Immunofluorescence, immunoprecipitation, and protein sequencing studies identified the target antigen of 5E2 mAb as the 86-kD subunit of the Ku autoantigen. We demonstrate that increased cell surface expression of Ku on CD40L-treated cells is due to migration of Ku from the cytoplasm to the cell surface membrane. Moreover, cell surface Ku on CD40L-treated MM cells mediates homotypic adhesion of tumor cells, as well as heterotypic adhesion of tumor cells to bone marrow stromal cells and to human fibronectin; and 5E2 mAb abrogates IL-6 secretion triggered by tumor cell adherence to bone marrow stromal cells. These data suggest that CD40L treatment induces a shift of Ku from the cytoplasm to the cell surface, and are the first to show that Ku functions as an adhesion molecule. They further suggest that cell surface Ku may play a role in both autocrine and paracrine IL-6-mediated MM cell growth and survival.
c‐Rel–dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis
Authors: Jack Leslie, Jill E. Hunter, Amy Collins, Amelia Rushton, Lauren G. Russell, Erik Ramon‐Gil, Maja Laszczewska, Misti McCain, Marco Y. W. Zaki, Amber Knox, Yixin Seow, Laura Sabater, Daniel Geh, Neil D. Perkins, Helen L. Reeves, Dina Tiniakos, Derek A. Mann, Fiona Oakley
Journal: Hepatology (2022)

Background and Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related death. The NF‐κB transcription factor family subunit c‐Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c‐Rel in HCC. Approach and Results: Histological and transcriptional studies confirmed expression of c‐Rel in human patients with HCC, but low c‐Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo , global ( Rel −/− ) and epithelial specific ( Rel Alb ) c‐Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild‐type (WT) controls 30 weeks after N‐diethylnitrosamine injury. However, tumor burden was comparable when c‐Rel was deleted in hepatocytes once tumors were established, suggesting c‐Rel signaling is important for preventing HCC initiation after genotoxic injury, rather than for HCC progression. In vitro , Rel −/− hepatocytes were more susceptible to genotoxic injury than WT controls. ATM‐CHK2 DNA damage response pathway proteins were suppressed in Rel −/− hepatocytes following genotoxic injury, suggesting that c‐Rel is required for effective DNA repair. To determine if c‐Rel inhibition sensitizes cancer cells to chemotherapy, by preventing repair of chemotherapy‐induced DNA damage, thus increasing tumor cell death, we administered single or combination doxorubicin and IT‐603 (c‐Rel inhibitor) therapy in an orthotopic HCC model. Indeed, combination therapy was more efficacious than doxorubicin alone. Conclusion: Hepatocyte c‐Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c‐Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.
The Infertile Couple
Authors: Howard W. Jones, James P. Toner
Journal: New England Journal of Medicine (1993)

Most adults have life plans that include children. When those who desire children find their efforts unsuccessful, frustration, despair, and helplessness are common and debilitating consequences. In this article we survey the scope of the problem of infertility, its current therapies, and the future prospects.Scope of the ProblemIn the United States, surveys conducted by the National Center for Health Statistics estimate that in 1988, 8.4 percent of women 15 to 44 years of age, or 4.9 million women, had an impaired ability to have children1. Of these women, 2.2 million had no children (primary infertility), and 2.7 . . .
The gut microbiome molecular complex in human health and disease
Authors: Paul Wilmes, Camille Martin-Gallausiaux, Marek Ostaszewski, Velma T.E. Aho, Polina V. Novikova, Cédric C. Laczny, Jochen G. Schneider
Journal: Cell Host & Microbe (2022)

The human gut microbiome produces a functional complex of biomolecules, including nucleic acids, (poly) peptides, structural molecules, and metabolites.This impacts human physiology in multiple ways, especially by triggering inflammatory pathways in disease.At present, much remains to be learned about the identity of key effectors and their causal roles.
Neisseria species as pathobionts in bronchiectasis
Authors: Liang Li, Micheál Mac Aogáin, Tengfei Xu, Tavleen Kaur Jaggi, Louisa L.Y. Chan, Jing Qu, Lan Wei, Shumin Liao, Hong Sheng Cheng, Holly R. Keir, Alison J. Dicker, Kai Sen Tan, Wang De Yun, Mariko Siyue Koh, Thun How Ong, Albert Yick Hou Lim, John A. Abisheganaden, Teck Boon Low, Tidi Maharani Hassan, Xiang Long, Peter A.B. Wark, Brian Oliver, Daniela I. Drautz-Moses, Stephan C. Schuster, Nguan Soon Tan, Mingliang Fang, James D. Chalmers, Sanjay H. Chotirmall
Journal: Cell Host & Microbe (2022)

Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group.
Dual genome-wide coding and lncRNA screens in neural induction of induced pluripotent stem cells
Authors: David Wu, Aunoy Poddar, Elpiniki Ninou, Elizabeth Hwang, Mitchel A. Cole, S. John Liu, Max A. Horlbeck, Jin Chen, Joseph M. Replogle, Giovanni A. Carosso, Nicolas W.L. Eng, Jonghoon Chang, Yin Shen, Jonathan S. Weissman, Daniel A. Lim
Journal: Cell Genomics (2022)

Human chromosomes are pervasively transcribed, but systematic understanding of coding and lncRNA genome function in cell differentiation is lacking. Using CRISPR interference (CRISPRi) in human induced pluripotent stem cells, we performed dual genome-wide screens - assessing 18,905 protein-coding and 10,678 lncRNA loci - and identified 419 coding and 201 lncRNA genes that regulate neural induction. Integrative analyses revealed distinct properties of coding and lncRNA genome function, including a 10-fold enrichment of lncRNA genes for roles in differentiation compared to proliferation. Further, we applied Perturb-seq to obtain granular insights into neural induction phenotypes. While most coding hits stalled or aborted differentiation, lncRNA hits were enriched for the genesis of diverse cellular states, including those outside the neural lineage. In addition to providing a rich resource (danlimlab.shinyapps.io/dualgenomewide) for understanding coding and lncRNA gene function in development, these results indicate that the lncRNA genome regulates lineage commitment in a manner fundamentally distinct from coding genes.
SnapShot: The Expobiome Map
Authors: Velma T.E. Aho, Marek Ostaszewski, Camille Martin-Gallausiaux, Cédric C. Laczny, Jochen G. Schneider, Paul Wilmes
Journal: Cell Host & Microbe (2022)

The human gut microbiome is intricately connected to health and disease. Microbiome-derived molecules are implicated in many chronic diseases involving inflammation. Herein, we summarize the diverse complex of such immunogenic molecules, including nucleic acids, (poly)peptides, structural molecules, and metabolites. The interactions between this "expobiome" and human immune pathways are specifically illustrated in the context of chronic diseases. To view this SnapShot, open or download the PDF.
Relationships of Serum 25-Hydroxyvitamin D Concentrations, Diabetes, Genetic Susceptibility, and New-Onset Chronic Kidney Disease
Authors: Chun Zhou, Panpan He, Ziliang Ye, Yuanyuan Zhang, Yanjun Zhang, Sisi Yang, Qimeng Wu, Mengyi Liu, Jing Nie, Xianhui Qin
Journal: Diabetes Care (2022)

OBJECTIVE The prospective relation of vitamin D status with the risk of chronic kidney diseases (CKD) remains uncertain. We aimed to examine the association of serum 25-hydroxyvitamin D (25OHD) with new-onset CKD in participants with and without diabetes at baseline and examine the potential modifications by genetic susceptibility on the association. RESEARCH DESIGN AND METHODS Included were 348,243 adults from the UK Biobank without prior CKD at baseline. Serum 25OHD concentrations were measured by chemiluminescent immunoassay method. Genetic risk score of CKD was calculated by 263 single nucleotide polymorphisms, which showed significant associations with estimated glomerular filtration rate. The primary outcome was new-onset CKD. RESULTS During a median follow-up duration of 12.1 years, 9,344 new-onset CKD were documented. Overall, there was a significant inverse association between baseline serum 25OHD and new-onset CKD in participants with diabetes (per SD increment, adjusted hazard ratio [HR] 0.91; 95% CI 0.86–0.96), but not in those without diabetes (per SD increment, adjusted HR 0.98; 95% CI 0.96–1.01; P-interaction between serum 25OHD and diabetes = 0.004). Accordingly, among participants with diabetes, compared with those baseline serum 25OHD &amp;lt;25 nmol/L, a significantly lower risk of new-onset CKD was found in those with 25OHD ≥50 nmol/L (adjusted HR 0.77; 95% CI 0.67–0.89). Moreover, the genetic risk of CKD did not significantly modify the association between baseline serum 25OHD and new-onset CKD among participants with diabetes (P-interaction = 0.127). CONCLUSIONS There was an inverse association between baseline serum 25OHD and new-onset CKD in participants with diabetes. The inverse association was not found in participants without diabetes.
Rachel Clarke: We should judge Coffey on her policies, not her appearance
Authors: Rachel Clarke
Journal: BMJ (2022)

Recent studies have reported that the application of thermal energy delivered through a bronchoscope (bronchial thermoplasty) impairs the ability of airways to narrow in response to methacholine. How such altered smooth muscle affects the response of airways to lung inflation may have important clinical implications, particularly as it relates to the abnormal response of asthmatic subjects to lung inflation and deep inspiration. The aim of this study was to examine whether bronchial thermoplasty affected airway distension with lung inflation in relaxed and contracted airways. A total of 230 airways were studied, ranging 2.5–15 mm, in six dogs. These airways were divided into two groups: an untreated (control) population and a bronchial thermoplasty-treated population. Prior to treatment, the airway pressure-area curves in the two groups of airways were identical. In contrast, the relaxed and contracted airway pressure-area curves in treated airways were shifted upward at all points, showing increased airway area at both 3 and 5 weeks post-treatment. In conclusion, these results show that reducing that amount of functional smooth muscle with bronchial thermoplasty leads to increased airway size in both relaxed and contracted states over a normal range of inflation pressures.
Scarlett McNally: Healthcare isn’t about one-off heroic interventions
Authors: Scarlett McNally
Journal: BMJ (2022)

Being a surgeon is a huge privilege.Each patient puts their trust in you and the perioperative team.There are hours, days, even months of planning-all for the critical minutes of concentration in the operating theatre.Minutes when everyone is focused on one outcome and you have everything you need: lighting, equipment, position.It's all "perfect."The whole team's efforts-before, during, and after the operation-enable the surgeon to do their very best.All those years spent acquiring knowledge, skills, and experience pay off.For surgery, read any intervention: the same applies to operations, radiologically guided interventions, clot busting, or delivering babies.